The observation that atherosclerotic plaques are monoclonal in origin suggests that atherosclerotic plaques, like cancer, may arise by somatic mutation. The fact that both carcinogens and an oncogenic virus increase atherosclerosis in chickens adds further evidence that environmental mutagens may be a significant factor in the etiology of antherosclerosis. This proposal is designed as a further test of the hypothesis that an atherosclerotic plaque begins as a somatic mutation. The experimental approach depends upon the use of the Ah locus in inbred strains of mice. This locus determines the inducibility of enzymes which metabolize polycyclic aromatic hydrocarbons to mutagenic products. When mice are treated with the carcinogens 3-methylcholanthrene (3-MC), Ah-inducible animals get more tumors than Ah-noninducible mice. We propose to induce atherosclerosis in both Ah-inducible and Ah-noninuducible strains of mice using an atherogenic diet for all mice and treating half the mice in each group with 3-MC. If the hypothesis that mutagens initiate atherosclerotic plaques is true, then two experimental results are predicted by the hypothesis. First, mice treated with 3-MC will have more atherosclerosis than mice fed atherogenic diet only. Second, in the 3-MC treated groups, Ah-inducible mice will have more atherosclerosis than Ah-noninducible mice because the Ah-inducible mice will metabolize more of the chemical to the mutagenic form. If mutagens do cause atherosclerosis in mice, several additional questions will be asked. Does susceptibility to atherosclerosis segregate with the Ah locus? Does 3-MC act as an initiator in plaque formation or can its role be explained by a promotor effect? Are plaques in the mouse monoclonal in origin? This question can be answered using one of the X-linked biochemical variants.